Postural tachycardia syndrome (POTS) is the most common cause of chronic orthostatic intolerance affecting at least one million Americans. POTS is not a single disease but rather a pathophysiological category characterized by decreased cardiac venous return related to impaired vascular regulation. Our long-term objective is to identify and treat vascular dysfunction in POTS. Preliminary data indicate that POTS in the young segregates into three groups: a) reduced adrenergic-mediated vasoconstriction producing peripheral vasodilation; b) defective splanchnic venoconstriction producing venous pooling; and c) abnormal local vascular control producing peripheral arterial vasoconstriction, venoconstriction and decreased peripheral blood flow. This last group is the focus of the current proposal. We hypothesize that local vascular defects relate to endothelial dysfunction and reduced nitric oxide (NO) secretion which is demonstrable in the skin. We will identify 30 low flow POTS patients and 30 high flow POTS patients by upright tilt tests of 200 potential subjects comparing them to 30 healthy volunteers: 1) To test the hypothesis that local NO release is impaired we will use laser Doppler flowmetry (LDF) combined with reactive hyperemia and thermal hyperemia measurements (local heating to 42 degrees C) to show defective flow mediated vasodilation. We predict reduced tissue levels of NO metabolites (NOx) by microdialysis, decreased effects of the NO synthase inhibitor nitro-L-arginine (NLA) on NOx production and LDF, and blunted dose-response to cutaneous acetylcholine but not to sodium nitroprusside (SNP) as receptor mediated endothelial-dependent and independent vasodilators; we will determine if local SNP restores flow mediated hyperemia; and we will administer phentolamine to verify that adrenergic mechanisms are not the primary cause of vasoconstriction. 2) We will use intravital microscopy of the hand and foot nailbeds to test for microanatomic evidence of vasoconstriction and venoconstriction related to microvascular size or enhanced leukocyte adhesion. 3) We will test the hypotheses that calf venous hypertension, venous capacitance and venous resistance are related to local vascular dysfunction by measuring blood volume, fractional excretion of sodium, vascular capacitance, peripheral blood flow, arterial and venous resistance, and local vascular properties in the forearm and calf and relate these to microvascular measurements using venous occlusion plethysmography in the forearm and calf. Verifying these hypotheses will improve our ability to diagnose and treat an important cause of vascular pathophysiology in man.